EP2263650A2 - Nanopartikuläre Megestrol- Formulierungen - Google Patents

Nanopartikuläre Megestrol- Formulierungen Download PDF

Info

Publication number
EP2263650A2
EP2263650A2 EP10010939A EP10010939A EP2263650A2 EP 2263650 A2 EP2263650 A2 EP 2263650A2 EP 10010939 A EP10010939 A EP 10010939A EP 10010939 A EP10010939 A EP 10010939A EP 2263650 A2 EP2263650 A2 EP 2263650A2
Authority
EP
European Patent Office
Prior art keywords
less
megestrol
composition
ammonium chloride
nanoparticulate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10010939A
Other languages
English (en)
French (fr)
Other versions
EP2263650A3 (de
Inventor
designation of the inventor has not yet been filed The
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alkermes Pharma Ireland Ltd
Original Assignee
Elan Pharma International Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Elan Pharma International Ltd filed Critical Elan Pharma International Ltd
Publication of EP2263650A2 publication Critical patent/EP2263650A2/de
Publication of EP2263650A3 publication Critical patent/EP2263650A3/de
Withdrawn legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a nanoparticulate composition
  • a nanoparticulate composition comprising megestrol and preferably at least one surface stabilizer associated with the surface of the drug.
  • the nanoparticulate megestrol particles have an effective average particle size of less than about 2000 nm.
  • Nanoparticulate compositions are particles consisting of a poorly soluble therapeutic or diagnostic agent having adsorbed onto the surface thereof a non-crosslinked surface stabilizer.
  • the '684 patent does not describe nanoparticulate compositions of megestrol.
  • Nanoparticulate compositions are also described, for example, in U.S. Patent Nos. 5,298,262 for "Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;" 5,302,401 for “Method to Reduce Particle Size Growth During Lyophilization;” 5,318,767 for “X-Ray Contrast Compositions Useful in Medical Imaging;” 5,326,552 for “Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;” 5,328,404 for “Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates;” 5,336,507 for “Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;” 5,340,564 for “Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability;” 5,346,702 for "Use of Non-Ionic Cloud Point Mod
  • Amorphous small particle compositions are described, for example, in U.S. Patent Nos. 4,783,484 for "Particulate Composition and Use Thereof as Antimicrobial Agent;” 4,826,689 for “Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds;” 4,997,454 for “Method for Making Uniformly-Sized Particles From Insoluble Compounds;” 5,741,522 for "Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods;” and 5,776,496 , for "Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter.”
  • Megestrol acetate also known as 17 ⁇ -acetyloxy-6-methylpregna-4,6-diene-3,20-dione, is a synthetic progestin with progestational effects similar to those of progesterone. It is used in abortion, endometriosis, and menstrual disorders. It is also used in a variety of situations including treatment of breast cancer, contraception, and hormone replacement therapy in post-menopausal women. Megestrol acetate is also frequently prescribed as an appetite enhancer for patients in a wasting state, such as HIV wasting, cancer wasting, or anorexia. In combination with ethynyl estradiol it acts as an oral contraceptive. It is also administered to subjects after castration.
  • Megestrol acetate is marketed by Par Pharmaceuticals, Inc. and under the brand name Megace® by Bristol Myers Squibb Co. Typical commercial formulations are relatively large volume.
  • Par Pharmaceuticals, Inc. megestrol acetate oral suspension contains 40 mg of micronized megestrol acetate per ml, and the package insert recommends an initial adult dosage of megestrol acetate oral suspension of 800 mg/day (20 mL/day).
  • the commercial formulations of megestrol acetate are highly viscous suspensions, which have a relatively long residence time in the mouth and any tubing. Highly viscous substances are not well accepted by patient populations, particularly patients suffering wasting and those that are intubated.
  • the compositions comprise at least one compound selected from the group consisting of polyethylene glycol, propylene glycol, glycerol, and sorbitol; and a surfactant, wherein polysorbate and polyethylene glycol are not simultaneously present.
  • 6,268,356 also for "Flocculated Suspension of Megestrol Acetate," and assigned to Pharmaceutical Resources, Inc., describes methods of treating a neoplastic condition comprising administering the composition of U.S. Patent No. 6,028,065 .
  • Eurand Another company that has developed a megestrol formulation is Eurand (Milan, Italy). Eurand's formulation is a modified form of megestrol acetate having increased bioavailability. Eurand structurally modifies poorly soluble drugs to increase their bioavailability. See www.eurand.com. For megestrol acetate, Eurand uses its' "Biorise” process, in which a New Physical Entity (NPE) is created by physically breaking down megestrol's crystal lattice. This results in drug nanocrystals and/or amorphous drug, which are then stabilized with biologically inert carriers.
  • NPE New Physical Entity
  • megestrol acetate is one of the few that can be administered orally because of its reduced first-pass (hepatic) metabolism, compared to the parent hormone.
  • megestrol acetate is claimed to be superior to 19-nor compounds as an antifertility agent because it has less effect on the endometrium and vagina. See Stedman's Medical Dictionary, 25th Ed., page 935 (Williams & Wilkins, MD 1990 ).
  • megestrol formulations which exhibit increased bioavailability, less variability, and/or less viscosity as compared to conventional microparticulate megestrol formulations.
  • the present invention satisfies these needs.
  • the invention relates to nanoparticulate megestrol compositions.
  • the compositions comprise megestrol and preferably at least one surface stabilizer associated with the surface of the megestrol particles.
  • the nanoparticulate megestrol particles have an effective average particle size of less than about 2000 nm.
  • compositions comprising a nanoparticulate megestrol composition of the invention.
  • the pharmaceutical compositions preferably comprise megestrol, at least one surface stabilizer, and a pharmaceutically acceptable carrier, as well as any desired excipients.
  • This invention further discloses a method of making a nanoparticulate megestrol composition according to the invention.
  • Such a method comprises contacting megestrol particles and at least one surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate megestrol composition.
  • the one or more surface stabilizers can be contacted with megestrol either before, during, or after size reduction of the megestrol.
  • the present invention is also directed to methods of treatment using the nanoparticulate compositions of the invention for conditions such as endometriosis, dysmenorrhea, hirsutism, uterine bleeding, neoplastic diseases, methods of appetite enhancement, contraception, hormone replacement therapy, and treating patients following castration.
  • Such methods comprises administering to a subject a therapeutically effective amount of a nanoparticulate megestrol composition according to the invention.
  • the present invention is directed to megestrol acetate compositions with improved physical (viscosity) and pharmacokinetic profiles (such as less variability) over traditional forms of megestrol acetate.
  • the present invention is directed to nanoparticulate compositions comprising megestrol particles having an effective average particle size of less than about 2 microns.
  • the compositions comprise megestrol and preferably at least one surface stabilizer associated with the surface of the drug.
  • Nanoparticulate megestrol compositions with hydroxypropyl methylcellulose (HPMC) and sodium lauryl sulfate (SLS) as surface stabilizers remained stable in an electrolyte solution mimicking the physiological pH of the stomach.
  • Nanoparticulate megestrol compositions comprising HPMC and SLS are stable for several weeks at temperatures up to 40°C with only minimal particle size growth.
  • nanoparticulate megestrol compositions with hydroxypropylcellulose (HPC) and dioctyl sodium sulfosuccinate (DOSS) as surface stabilizers HPMC and DOSS as surface stabilizers, polyvinylpyrrolidone (PVP) and DOSS as surface stabilizers, and Plasdone® S630 and DOSS as surface stabilizers were stable in electrolyte fluids and exhibited acceptable physical stability at 5°C for 4 weeks.
  • nanoparticulate megestrol/HPMC/SLS and nanoparticulate megestrol/HPMC/DOSS compositions also exhibited acceptable physical stability at 25°C and 40°C for 4 weeks.
  • nanoparticulate megestrol compositions of the invention include, but are not limited to: (1) low viscosity liquid nanoparticulate megestrol dosage forms; (2) for liquid nanoparticulate megestrol compositions having a low viscosity - better subject compliance due to the perception of a lighter formulation which is easier to consume and digest; (3) for liquid nanoparticulate megestrol compositions having a low viscosity - ease of dispensing because one can use a cup or a syringe; (4) faster onset of action; (5) smaller doses of megestrol required to obtain the same pharmacological effect as compared to conventional microcrystalline forms of megestrol; (6) increased bioavailability as compared to conventional microcrystalline forms of megestrol; (7) substantially similar pharmacokinetic profiles of the nanoparticulate megestrol compositions when administered in the fed versus the fasted state; (8) bioequivalency of the nanoparticulate megestrol compositions when administered in the fed versus the fasted state
  • stable means that the megestrol particles do not appreciably flocculate or agglomerate due to interparticle attractive forces or otherwise increase in particle size.
  • Non-nanoparticulate active agents refers to non-nanoparticulate compositions of active agents or solubilized active agents or drugs.
  • Non-nanoparticulate active agents have an effective average particle size of greater than about 2 microns.
  • Typical commercial formulations of megestrol such as Megace®, are relatively large volume, highly viscous substances that are not well accepted by patient populations, particularly subjects suffering from wasting. "Wasting” is a condition in which a subject finds it difficult to eat because, for example, food makes the subject nauseous. A highly viscous medicine is not compatible with treating such a condition, as frequently the highly viscous substance can cause additional nausea.
  • viscous solutions can be problematic in parenteral administration because these solutions require a slow syringe push and can stick to tubing.
  • conventional formulations of poorly water-soluble active agents, such as megestrol tend to be unsafe for intravenous administration techniques, which are used primarily in conjunction with highly water-soluble substances.
  • Liquid dosage forms of the nanoparticulate megestrol compositions of the invention provide significant advantages over conventional liquid megestrol dosage forms.
  • the low viscosity and silky texture of liquid dosage forms of the nanoparticulate megestrol compositions of the invention results in advantages in both preparation and use. These advantages include, for example: (1) better subject compliance due to the perception of a lighter formulation which is easier to consume and digest; (2) ease of dispensing because one can use a cup or a syringe; (3) potential for formulating a higher concentration of megestrol resulting in a smaller dosage volume and thus less volume for the subject to consume; and (4) easier overall formulation concerns.
  • Liquid megestrol dosage forms which are easier to consume are especially important when considering juvenile patients, terminally ill patients, and patients suffering from gastrointestinal tract dysfunction or other conditions where nausea and vomiting are symptoms.
  • patients suffering from cancer or AIDS-related complications are commonly hypermetabolic and, at various stages of disease, exhibit gastrointestinal dysfunction.
  • drugs used to treat these conditions often cause nausea and vomiting. Viscous or gritty formulations, and those that require a relatively large dosage volume, are not well tolerated by patient populations suffering from wasting associated with these diseases because the formulations can exacerbate nausea and encourage vomiting.
  • the viscosities of liquid dosage forms of nanoparticulate megestrol according to the invention are preferably less than about 1/200, less than about 1/175, less than about 1/150, less than about 1/125, less than about 1/100, less than about 1/75, less than about 1/50, or less than about 1/25 of existing commercial liquid oral megestrol acetate compositions, e.g . Megace®, at about the same concentration per ml of megestrol.
  • the viscosity of liquid nanoparticulate megestrol dosage forms of the invention is from about 175 mPa s to about 1 mPa s, from about 150 mPa s to about 1 mPa, from about 125 mPa s to about 1 mPa s, from about 100 mPa s to about 1 mPa s, from about 75 mPa s to about 1 mPa s, from about 50 mPa s to about 1 mPa s, from about 25 mPa s to about 1 mPa s, from about 15 mPa s to about 1 mPa s, or from about 5 mPa s to about 1 mPa s.
  • Such a viscosity is much more attractive for subject consumption and may lead to better overall subject compliance.
  • Viscosity is concentration and temperature dependent. Typically, a higher concentration results in a higher viscosity, while a higher temperature results in a lower viscosity. Viscosity as defined above refers to measurements taken at about 20°C. (The viscosity of water at 20°C is 1 mPa s.) The invention encompasses equivalent viscosities measured at different temperatures.
  • nanoparticulate megestrol compositions of the invention are not turbid.
  • "Turbid,” as used herein refers to the property of particulate matter that can be seen with the naked eye or that which can be felt as “gritty.”
  • the nanoparticulate megestrol compositions of the invention can be poured out of or extracted from a container as easily as water, whereas a conventional standard commercial (i.e ., non-nanoparticulate or solubilized) megestrol liquid dosage form exhibits notably more "sluggish" characteristics.
  • liquid formulations of this invention can be formulated for dosages in any volume but preferably equivalent or smaller volumes than existing commercial formulations.
  • the nanoparticulate megestrol compositions of the invention have a T max of less than about 5 hours, less than about 4.5 hours, less than about 4 hours, less than about 3.5 hours, less than about 3 hours, less than about 2.75 hours, less than about 2.5 hours, less than about 2.25 hours, less than about 2 hours, less than about 1.75 hours, less than about 1.5 hours, less than about 1.25 hours, less than about 1.0 hours, less than about 50 minutes, less than about 40 minutes, less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, or less than about 10 minutes.
  • the nanoparticulate megestrol compositions of the invention preferably exhibit increased bioavailability and require smaller doses as compared to prior conventional megestrol compositions administered at the same dose.
  • any drug including megestrol
  • lower doses of megestrol which can achieve the same or better therapeutic effects as those observed with larger doses of conventional megestrol compositions are desired.
  • Such lower doses can be realized with the nanoparticulate megestrol compositions of the invention because the greater bioavailability observed with the nanoparticulate megestrol compositions as compared to conventional drug formulations means that smaller does of drug are required to obtain the desired therapeutic effect.
  • a once a day dose of about 375 mg/5 mL (75 mg/mL) of a nanoparticulate megestrol acetate composition is considered equivalent to an 800 mg dose of Megace®.
  • nanoparticulate megestrol formulations of the present invention can exhibit bioavailability, as determined by AUC0-t, in an amount of about 3000 ng hr/ml to about 10,000 ng hr/ml, wherein Cmax is about 300 ng/ml to about 1100 ng/ml in a fed human subject and AUC0-t in an amount of about 2000 ng hr/ml to about 9000 ng hr/ml, wherein Cmax is about 300 ng/ml to about 2000 ng/ml in a fasted human subject.
  • nanoparticulate megestrol formulations of the present invention exhibit comparable bioavailability in a range of between about 75 and about 130%, more preferably between about 80% and about 125%, of the specified therapeutic parameter (e.g., AUC0-t or Cmax).
  • the specified therapeutic parameter e.g., AUC0-t or Cmax.
  • the invention encompasses nanoparticulate megestrol compositions wherein the pharmacokinetic profile of the megestrol is not substantially affected by the fed or fasted state of a subject ingesting the composition. This means that there is no substantial difference in the quantity of megestrol absorbed or the rate of megestrol absorption when the nanoparticulate megestrol compositions are administered in the fed versus the fasted state.
  • the nanoparticulate megestrol compositions of the invention substantially eliminate the effect of food on the pharmacokinetics of megestrol.
  • the difference in absorption of the nanoparticulate megestrol composition of the invention, when administered in the fed versus the fasted state, is less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3%. This is an especially important feature in treating patients with difficulty in maintaining a fed state.
  • the difference in the rate of absorption (i.e ., T max ) of the nanoparticulate megestrol compositions of the invention, when administered in the fed versus the fasted state is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, or essentially no difference.
  • Benefits of a dosage form which substantially eliminates the effect of food include an increase in subject convenience, thereby increasing subject compliance, as the subject does not need to ensure that they are taking a dose either with or without food.
  • compositions of the invention redisperse such that the effective average particle size of the redispersed megestrol particles is less than about 2 microns. This is significant, as if upon administration the nanoparticulate megestrol particles present in the compositions of the invention did not redisperse to a substantially nanoparticulate particle size, then the dosage form may lose the benefits afforded by formulating megestrol into a nanoparticulate particle size.
  • nanoparticulate megestrol compositions benefit from the small particle size of megestrol; if the nanoparticulate megestrol particles do not redisperse into the small particle sizes upon administration, then "clumps" or agglomerated megestrol particles are formed. With the formation of such agglomerated particles, the bioavailability of the dosage form may fall.
  • the redispersed megestrol particles of the invention have an effective average particle size, by weight, of less than about 2 microns, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm, as measured by light-scattering methods, microscopy, or other appropriate methods.
  • the nanoparticulate megestrol compositions of the invention exhibit dramatic redispersion of the nanoparticulate megestrol particles upon administration to a mammal, such as a human or animal, as demonstrated by reconstitution in a biorelevant aqueous media.
  • biorelevant aqueous media can be any aqueous media that exhibit the desired ionic strength and pH, which form the basis for the biorelevance of the media.
  • the desired pH and ionic strength are those that are representative of physiological conditions found in the human body.
  • Such biorelevant aqueous media can be, for example, aqueous electrolyte solutions or aqueous solutions of any salt, acid, or base, or a combination thereof, which exhibit the desired pH and ionic strength.
  • Biorelevant pH is well known in the art.
  • the pH ranges from slightly less than 2 (but typically greater than 1) up to 4 or 5.
  • the pH can range from 4 to 6, and in the colon it can range from 6 to 8.
  • Biorelevant ionic strength is also well known in the art. Fasted state gastric fluid has an ionic strength of about 0.1M while fasted state intestinal fluid has an ionic strength of about 0.14. See e.g ., Lindahl et al., "Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women," Pharm. Res., 14 (4): 497-502 (1997 ).
  • pH and ionic strength of the test solution is more critical than the specific chemical content. Accordingly, appropriate pH and ionic strength values can be obtained through numerous combinations of strong acids, strong bases, salts, single or multiple conjugate acid-base pairs ( i.e ., weak acids and corresponding salts of that acid), monoprotic and polyprotic electrolytes, etc .
  • electrolyte solutions can be, but are not limited to, HCI solutions, ranging in concentration from about 0.001 to about 0.1 M, and NaCl solutions, ranging in concentration from about 0.001 to about 0.1 M, and mixtures thereof.
  • electrolyte solutions can be, but are not limited to, about 0.1 M HCl or less, about 0.01 M HCl or less, about 0.001 M HCl or less, about 0.1 M NaCl or less, about 0.01 M NaCl or less, about 0.001 M NaCl or less, and mixtures thereof.
  • 0.01 M HCl and/or 0.1 M NaCl are most representative of fasted human physiological conditions, owing to the pH and ionic strength conditions of the proximal gastrointestinal tract.
  • Electrolyte concentrations of 0.001 M HCl, 0.01 M HCl, and 0.1 M HCl correspond to pH 3, pH 2, and pH 1, respectively.
  • a 0.01 M HCl solution simulates typical acidic conditions found in the stomach.
  • a solution of 0.1 M NaCl provides a reasonable approximation of the ionic strength conditions found throughout the body, including the gastrointestinal fluids, although concentrations higher than 0.1 M may be employed to simulate fed conditions within the human GI tract.
  • Exemplary solutions of salts, acids, bases or combinations thereof, which exhibit the desired pH and ionic strength include but are not limited to phosphoric acid/phosphate salts + sodium, potassium and calcium salts of chloride, acetic acid/acetate salts + sodium, potassium and calcium salts of chloride, carbonic acid/bicarbonate salts + sodium, potassium and calcium salts of chloride, and citric acid/citrate salts + sodium, potassium and calcium salts of chloride.
  • Bioadhesive nanoparticulate megestrol compositions of the invention comprise at least one cationic surface stabilizer, which are described in more detail below.
  • Bioadhesive formulations of megestrol exhibit exceptional bioadhesion to biological surfaces, such as mucous.
  • bioadhesive nanoparticulate megestrol compositions the term “bioadhesion” is used to describe the adhesion between the nanoparticulate megestrol compositions and a biological substrate (i.e . gastrointestinal mucin, lung tissue, nasal mucosa, etc .). See e.g ., U.S. Patent No. 6,428,814 for "Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers," which is specifically incorporated by reference.
  • bioadhesive megestrol compositions of the invention are useful in any situation in which it is desirable to apply the compositions to a biological surface.
  • the bioadhesive megestrol compositions coat the targeted surface in a continuous and uniform film which is invisible to the naked human eye.
  • a bioadhesive nanoparticulate megestrol composition slows the transit of the composition, and some megestrol particles would also most likely adhere to tissue other than the mucous cells and therefore give a prolonged exposure to megestrol, thereby increasing absorption and the bioavailability of the administered dosage.
  • the present invention also provides compositions of nanoparticulate megestrol having a desirable pharmacokinetic profile when administered to mammalian subjects.
  • the desirable pharmacokinetic profile of the nanoparticulate megestrol compositions comprise the parameters: (1) that the T max of megestrol, when assayed in the plasma of the mammalian subject, is less than about 5 hours; and (2) a C max of megestrol is greater than about 30 ng/ml.
  • the T max parameter of the pharmacokinetic profile is not greater than about 3 hours. Most preferably, the T max parameter of the pharmacokinetic profile is not greater than about 2 hours.
  • the desirable pharmacokinetic profile is the pharmacokinetic profile measured after the initial dose of megestrol.
  • the T max and C max after the initial dose must be less than about 5 hours and greater than about 30 ng/ml, respectively.
  • the compositions can be formulated in any way as described below.
  • megestrol Current formulations of megestrol include oral suspensions and tablets.
  • the pharmacokinetic profile of the oral suspension contains parameters such that the median T max is 5 hours and the mean C max is 753 ng/ml. Further, the T max and C max for the Megace® 40 mg tablet, after the initial dose, is 2.2 hours and 27.6 ng/ml, respectively. Physicians Desk Reference , 55 th Ed., 2001.
  • the nanoparticulate megestrol compositions of the invention simultaneously improve upon at least the T max and C max parameters of the pharmacokinetic profile of megestrol.
  • a threshold blood plasma concentration of megestrol of about 700 ng/ml is attained in less than about 5 hours after administration of the formulation, and preferably not greater than about 3 hours.
  • the T max of an administered dose of a nanoparticulate megestrol composition is less than that of a conventional standard commercial non-nanoparticulate megestrol composition, administered at the same dosage.
  • the C max of a nanoparticulate megestrol composition is greater than the C max of a conventional standard commercial non-nanoparticulate megestrol composition, administered at the same dosage.
  • a preferred nanoparticulate megestrol composition of the invention exhibits in comparative pharmacokinetic testing with a standard commercial formulation of megestrol, such as Megace® oral suspension or tablet from Bristol Myers Squibb, a T max which is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, or less than about 10% of the T max exhibited by the standard commercial formulation of megestrol.
  • a standard commercial formulation of megestrol such as Megace® oral suspension or tablet from Bristol Myers Squibb, a T max which is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, or less than about 10% of the T max exhibited by the standard commercial formulation of megestrol.
  • a preferred nanoparticulate megestrol composition of the invention exhibits in comparative pharmacokinetic testing with a standard commercial formulation of megestrol, such as Megace® oral suspension or tablet from Bristol Myers Squibb, a C max which is greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, greater than about 100%, greater than about 110%, greater than about 120%, greater than about 130%, greater than about 140%, or greater than about 150% than the C max exhibited by the standard commercial formulation of megestrol.
  • a standard commercial formulation of megestrol such as Megace® oral suspension or tablet from Bristol Myers Squibb
  • a C max which is greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than
  • a suitable dose of megestrol, administered according to the method of the invention is typically in the range of about 1 mg/day to about 1000 mg/day, or from about 40 mg/day to about 800 mg/day.
  • the therapeutically effective amount of the nanoparticulate megestrol compositions of the invention is 1/6, 1/5, 1 ⁇ 4, 1/3 rd , or 1 ⁇ 2 of the therapeutically effective amount of existing commercial megestrol formulations.
  • Any standard pharmacokinetic protocol can be used to determine blood plasma concentration profile in humans following administration of a nanoparticulate megestrol composition, and thereby establish whether that composition meets the pharmacokinetic criteria set out herein.
  • a randomized single-dose crossover study can be performed using a group of healthy adult human subjects. The number of subjects should be sufficient to provide adequate control of variation in a statistical analysis, and is typically about 10 or greater, although for certain purposes a smaller group can suffice.
  • Each subject receives by oral administration at time zero a single dose (e.g ., 300 mg) of a test formulation of megestrol, normally at around 8 am following an overnight fast. The subjects continue to fast and remain in an upright position for about 4 hours after administration of the megestrol formulation.
  • Blood samples are collected from each subject prior to administration (e.g ., 15 minutes) and at several intervals after administration. For the present purpose it is preferred to take several samples within the first hour, and to sample less frequently thereafter. Illustratively, blood samples could be collected at 15, 30, 45, 60, and 90 minutes after administration, then every hour from 2 to 10 hours after administration. Additional blood samples may also be taken later, for example at 12 and 24 hours after administration. If the same subjects are to be used for study of a second test formulation, a period of at least 7 days should elapse before administration of the second formulation.
  • Plasma is separated from the blood samples by centrifugation and the separated plasma is analyzed for megestrol by a validated high performance liquid chromatography (HPLC) procedure, such as for example Garver et al., J. Pharm. Sci. 74(6):664-667 (1985 ), the entirety of which is hereby incorporated by reference.
  • Plasma concentrations of megestrol referenced herein are intended to mean total megestrol concentrations including both free and bound megestrol.
  • any formulation giving the desired pharmacokinetic profile is suitable for administration according to the present methods.
  • Exemplary types of formulations giving such profiles are liquid dispersions and solid dose forms of nanoparticulate megestrol. Dispersions of megestrol have proven to be stable at temperatures up to 50°C. If the liquid dispersion medium is one in which the nanoparticulate megestrol has very low solubility, the nanoparticulate megestrol particles are present as suspended particles. The smaller the megestrol particles, the higher the probability that the formulation will exhibit the desired pharmacokinetic profile.
  • a first nanoparticulate megestrol composition providing a desired pharmacokinetic profile is co-administered, sequentially administered, or combined with at least one other megestrol composition that generates a desired different pharmacokinetic profile. More than two megestrol compositions can be co-administered, sequentially administered, or combined. While the first megestrol composition has a nanoparticulate particle size, the additional one or more megestrol compositions can be nanoparticulate, solubilized, or have a conventional microparticulate particle size.
  • a first megestrol composition can have a nanoparticulate particle size, conferring a short T max and typically a higher C max .
  • This first megestrol composition can be combined, co-administered, or sequentially administered with a second composition comprising: (1) megestrol having a larger (but still nanoparticulate as defined herein) particle size, and therefore exhibiting slower absorption, a longer T max , and typically a lower C max ; or (2) a microparticulate or solubilized megestrol composition, exhibiting a longer T max , and typically a lower C max .
  • the second, third, fourth, etc ., megestrol compositions can differ from the first, and from each other, for example: (1) in the effective average particle sizes of megestrol; or (2) in the dosage of megestrol. Such a combination composition can reduce the dose frequency required.
  • the megestrol particles of the second composition have at least one surface stabilizer associated with the surface of the drug particles.
  • the one or more surface stabilizers can be the same as or different from the surface stabilizer(s) present in the first megestrol composition.
  • the two formulations are combined within a single composition, for example a dual-release composition.
  • the invention encompasses the nanoparticulate megestrol compositions of the invention formulated or co-administered with one or more non-megestrol active agents, which are either conventional (solubilized or microparticulate) or nanoparticulate. Methods of using such combination compositions are also encompassed by the invention.
  • the non-megestrol active agents can be present in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, or a mixture thereof.
  • the compound to be administered in combination with a nanoparticulate megestrol composition of the invention can be formulated separately from the nanoparticulate megestrol composition or co-formulated with the nanoparticulate megestrol composition.
  • a nanoparticulate megestrol composition is co-formulated with a second active agent
  • the second active agent can be formulated in any suitable manner, such as immediate-release, rapid-onset, sustained-release, or dual-release form.
  • the non-megestrol active agent has a nanoparticulate particle size i.e ., a particle size of less than about 2 microns, then preferably it will have one or more surface stabilizers associated with the surface of the active agent.
  • the active agent has a nanoparticulate particle size, then it is preferably poorly soluble and dispersible in at least one liquid dispersion media.
  • “poorly soluble” it is meant that the active agent has a solubility in a liquid dispersion media of less than about 30 mg/mL, less than about 20 mg/mL, less than about 10 mg/mL, or less than about 1 mg/mL.
  • Useful liquid dispersion medias include, but are not limited to, water, aqueous salt solutions, safflower oil, and solvents such as ethanol, t-butanol, hexane, and glycol.
  • Such non-megestrol active agents can be, for example, a therapeutic agent.
  • a therapeutic agent can be a pharmaceutical agent, including biologics.
  • the active agent can be selected from a variety of known classes of drugs, including, for example, amino acids, proteins, peptides, nucleotides, anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sed
  • nutraceuticals and dietary supplements are disclosed, for example, in Roberts et al., Nutraceuticals: The Complete Encyclopedia of Supplements, Herbs, Vitamins, and Healing Foods (American Nutraceutical Association, 2001 ), which is specifically incorporated by reference. Dietary supplements and nutraceuticals are also disclosed in Physicians' Desk Reference for Nutritional Supplements, 1st Ed. (2001 ) and The Physicians' Desk Reference for Herbal Medicines, 1st Ed. (2001 ), both of which are also incorporated by reference.
  • a nutraceutical or dietary supplement, also known as a phytochemical or functional food is generally any one of a class of dietary supplements, vitamins, minerals, herbs, or healing foods that have medical or pharmaceutical effects on the body.
  • nutraceuticals or dietary supplements include, but are not limited to, lutein, folic acid, fatty acids (e.g ., DHA and ARA), fruit and vegetable extracts, vitamin and mineral supplements, phosphatidylserine, lipoic acid, melatonin, glucosamine/chondroitin, Aloe Vera, Guggul, glutamine, amino acids (e.g ., arginine, isoleucine, leucine, lysine, methionine, phenylanine, threonine, tryptophan, and valine), green tea, lycopene, whole foods, food additives, herbs, phytonutrients, antioxidants, flavonoid constituents of fruits, evening primrose oil, flax seeds, fish and marine animal oils, and probiotics. Nutraceuticals and dietary supplements also include bio-engineered foods genetically engineered to have a desired property, also known as "pharmafoods.”
  • nanoparticulate megestrol compositions of the invention can be sterile filtered. This obviates the need for heat sterilization, which can harm or degrade megestrol, as well as result in crystal growth and particle aggregation.
  • Sterile filtration can be difficult because of the required small particle size of the composition. Filtration is an effective method for sterilizing homogeneous solutions when the membrane filter pore size is less than or equal to about 0.2 microns (200 nm) because a 0.2 micron filter is sufficient to remove essentially all bacteria. Sterile filtration is normally not used to sterilize conventional suspensions of micron-sized megestrol because the megestrol particles are too large to pass through the membrane pores.
  • a sterile nanoparticulate megestrol dosage form is particularly useful in treating immunocompromised patients, infants or juvenile patients, and the elderly, as these patient groups are the most susceptible to infection caused by a non-sterile liquid dosage form.
  • nanoparticulate megestrol compositions of the invention can be sterile filtered, and because the compositions can have a very small megestrol effective average particle size, the compositions are suitable for parenteral administration.
  • the nanoparticulate megestrol compositions preferably exhibit an increased rate of dissolution as compared to conventional microcrystalline forms of megestrol.
  • the compositions of the invention exhibit improved performance characteristics for oral, intravenous, subcutaneous, or intramuscular injection, such as higher dose loading and smaller tablet or liquid dose volumes.
  • the nanoparticulate megestrol compositions of the invention do not require organic solvents or pH extremes.
  • nanoparticulate megestrol compositions of the invention Another benefit of the nanoparticulate megestrol compositions of the invention is that is was surprisingly discovered that upon administration, nanoparticulate compositions of megestrol acetate reach therapeutic blood levels within one dose. This is in dramatic contrast to the current commercially available megestrol acetate composition (Megace® by Bristol Myers Squibb Co.), which requires multiple doses, administered over several days to a week, to build up to a therapeutic level of drug in the blood stream.
  • compositions comprising nanoparticulate megestrol particles and preferably at least one surface stabilizer.
  • the one or more surface stabilizers are preferably associated with the surface of the megestrol particles.
  • Surface stabilizers useful herein preferably do not chemically react with the megestrol particles or itself. Individual molecules of the surface stabilizer are essentially free of intermolecular cross-linkages.
  • the present invention also includes nanoparticulate megestrol compositions together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles, collectively referred to as carriers.
  • the compositions can be formulated for parenteral injection (e.g ., intravenous, intramuscular, or subcutaneous), oral administration in solid, liquid, or aerosol form, vaginal, nasal, rectal, ocular, local (powders, ointments or drops), buccal, intracisternal, intraperitoneal, or topical administration, and the like.
  • megestrol which is the active ingredient in the composition, is used to mean megestrol, megestrol acetate (17 ⁇ -acetyloxy-6-methylpregna-4,6-diene-3,20-dione), or a salt thereof.
  • the megestrol particles can be present in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, or a mixture thereof.
  • Megestrol acetate is well known in the art and is readily recognized by one of ordinary skill. Generally, megestrol is used for treating breast cancer, endometrial cancer and, less frequently, prostate cancer. Megestrol is also frequently used as an appetite stimulant for patients in a wasting state, such as HIV wasting, cancer wasting, and anorexia. Megestrol may be used for other indications where progestins are typically used, such as hormone replacement therapy in post-menopausal women and oral contraception. Further, megestrol may be used for ovarian suppression in several conditions such as endometriosis, hirsutism, dysmenorrhea, and uterine bleeding, as well as uterine cancer, cervical cancer, and renal cancer. Megestrol is also used in patients following castration.
  • the choice of a surface stabilizer for megestrol is non-trivial. Accordingly, the present invention is directed to the surprising discovery that nanoparticulate megestrol compositions can be made.
  • Preferred surface stabilizers include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, random copolymers of vinyl pyrrolidone and vinyl acetate, sodium lauryl sulfate, dioctylsulfosuccinate or a combination thereof.
  • Preferred primary surface stabilizers include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, random copolymers of vinyl pyrrolidone and vinyl acetate, or a combination thereof.
  • Preferred secondary surface stabilizers include, but are not limited to, sodium lauryl sulfate and dioctylsulfosuccinate.
  • surface stabilizers which can be employed in the invention include, but are not limited to, known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Surface stabilizers include nonionic, cationic, ionic, and zwitterionic surfactants.
  • surface stabilizers include hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers ( e.g ., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters ( e.g ., the commercially available Tweens ® such as e.g ., Tween 20 ® and Tween 80 ® (ICI Speciality Chemicals)); polyethylene glycols (
  • cationic surface stabilizers include, but are not limited to, polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids, and nonpolymeric compounds, such as zwitterionic stabilizers, poly-n-methylpyridinium, anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate.
  • cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quarternary ammonium compounds, such as stearyltrimethylammonium chloride, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride or bromide, coconut methyl dihydroxyethyl ammonium chloride or bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, C 12-15 dimethyl hydroxyethyl ammonium chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl (ethenoxy) 4 ammonium chloride or bromide, N-
  • Such exemplary cationic surface stabilizers and other useful cationic surface stabilizers are described in J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994 ); P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991 ); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990 ).
  • nonpolymeric primary stabilizers are any nonpolymeric compound, such benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an ammonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and quarternary ammonium compounds of the formula NR 1 R 2 R 3 R 4 (+) .
  • benzalkonium chloride a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an ammonium compound, a hydroxylammonium compound, a primary am
  • Such compounds include, but are not limited to, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride(Quaternium-14), Quaternium-22, Quaternium-26, Quaternium-18 hectorite, dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oletyl ether phosphate, diethanolammonium POE (3)oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctadecylammoniumbento
  • compositions according to the invention may also comprise one or more binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other excipients.
  • excipients are known in the art.
  • filling agents are lactose monohydrate, lactose anhydrous, and various starches
  • binding agents are various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel ® PH101 and Avicel ® PH102, microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCCTM).
  • Suitable lubricants including agents that act on the flowability of the powder to be compressed, are colloidal silicon dioxide, such as Aerosil ® 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel.
  • sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame.
  • sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame.
  • flavoring agents are Magnasweet ® (trademark of MAFCO), bubble gum flavor, and fruit flavors, and the like.
  • preservatives examples include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quarternary compounds such as benzalkonium chloride.
  • Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing.
  • examples of diluents include microcrystalline cellulose, such as Avicel ® PH101 and Avicel ® PH102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose ® DCL21; dibasic calcium phosphate such as Emcompress ® ; mannitol; starch; sorbitol; sucrose; and glucose.
  • Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate, and mixtures thereof.
  • effervescent agents are effervescent couples such as an organic acid and a carbonate or bicarbonate.
  • Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts.
  • Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate.
  • sodium bicarbonate component of the effervescent couple may be present.
  • particle size is determined on the basis of the weight average particle size as measured by conventional particle size measuring techniques well known to those skilled in the art. Such techniques include, for example, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering, and disk centrifugation.
  • compositions of the invention comprise nanoparticulate megestrol particles which have an effective average particle size of less than about 2000 nm ( i.e ., 2 microns).
  • the megestrol particles have an effective average particle size of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, or less than about 50 nm
  • the nanoparticulate megestrol composition additionally comprises one or more non-megestrol nanoparticulate active agents, then such active agents have an effective average particle size of less than about 2000 nm ( i.e ., 2 microns).
  • the nanoparticulate non-megestrol active agents can have an effective average particle size of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm,
  • an effective average particle size of less than about 2000 nm it is meant that at least 50% of the nanoparticulate megestrol or nanoparticulate non-megestrol active agent particles have a particle size of less than about 2000 nm, by weight, when measured by the above-noted techniques.
  • at least about 70%, about 90%, about 95%, or about 99% of the nanoparticulate megestrol or nanoparticulate non-megestrol active agent particles have a particle size of less than the effective average, i.e ., less than about 2000 nm, less than about 1900 nm, less than about 1800 nm, etc .
  • nanoparticulate megestrol composition is combined with a conventional or microparticulate megestrol composition or non-megestrol active agent composition, then such a composition is either solubilized or has an effective average particle size of greater than about 2 microns.
  • an effective average particle size of greater than about 2 microns it is meant that at least 50% of the conventional megestrol or non-megestrol active agent particles have a particle size of greater than about 2 microns, by weight, when measured by the above-noted techniques. In other embodiments of the invention, at least about 70%, about 90%, about 95%, or about 99% of the conventional megestrol or non-megestrol active agent particles have a particle size greater than about 2 microns.
  • the relative amounts of nanoparticulate megestrol and one or more surface stabilizers can vary widely.
  • the optimal amount of the individual components can depend, for example, the hydrophilic lipophilic balance (HLB), melting point, and the surface tension of water solutions of the stabilizer, etc.
  • the concentration of megestrol can vary from about 99.5% to about 0.001%, from about 95% to about 0.1%, or from about 90% to about 0.5%, by weight, based on the total combined dry weight of the megestrol and at least one surface stabilizer, not including other excipients.
  • the concentration of the at least one surface stabilizer can vary from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, or from about 10% to about 99.5%, by weight, based on the total combined dry weight of the megestrol and at least one surface stabilizer, not including other excipients.
  • the concentration of the at least one primary surface stabilizer can vary from about 0.01% to about 99.5%, from about 0.1% to about 95%, or from about 0.5% to about 90%, by weight, based on the total combined dry weight of the megestrol, at least one primary surface stabilizer, and at least one secondary surface stabilizer, not including other excipients.
  • the concentration of the at least one secondary surface stabilizer can vary from about 0.01% to about 99.5%, from about 0.1% to about 95%, or from about 0.5% to about 90%, by weight, based on the total combined dry weight of the megestrol, at least one primary surface stabilizer, and at least one secondary surface stabilizer, not including other excipients.
  • nanoparticulate megestrol compositions can be made using, for example, milling, homogenization, or precipitation techniques. Exemplary methods of making nanoparticulate compositions are described in the '684 patent.
  • the resultant nanoparticulate megestrol compositions can be utilized in solid or liquid dosage formulations, such as controlled release formulations, solid dose fast melt formulations, aerosol formulations, lyophilized formulations, tablets, capsules, etc .
  • Milling megestrol to obtain a nanoparticulate megestrol dispersion comprises dispersing megestrol particles in a liquid dispersion medium in which megestrol is poorly soluble, followed by applying mechanical means in the presence of grinding media to reduce the particle size of megestrol to the desired effective average particle size.
  • the dispersion medium can be, for example, water, safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane, or glycol.
  • the megestrol particles can be reduced in size in the presence of at least one surface stabilizer.
  • the megestrol particles can be contacted with one or more surface stabilizers after attrition.
  • Other compounds, such as a diluent, can be added to the megestrol/surface stabilizer composition either before, during, or after the size reduction process.
  • Dispersions can be manufactured continuously or in a batch mode.
  • Another method of forming the desired nanoparticulate megestrol composition is by microprecipitation.
  • This is a method of preparing stable dispersions of poorly soluble active agents in the presence of one or more surface stabilizers and one or more colloid stability enhancing surface active agents free of any trace toxic solvents or solubilized heavy metal impurities.
  • Such a method comprises, for example: (1) dissolving megestrol in a suitable solvent; (2) adding the formulation from step (I) to a solution comprising at least one surface stabilizer; and (3) precipitating the formulation from step (2) using an appropriate non-solvent.
  • the method can be followed by removal of any formed salt, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means.
  • Such a method comprises dispersing megestrol particles in a liquid dispersion medium, followed by subjecting the dispersion to homogenization to reduce the particle size of the megestrol to the desired effective average particle size.
  • the megestrol particles can be reduced in size in the presence of at least one surface stabilizer.
  • the megestrol particles can be contacted with one or more surface stabilizers either before or after attrition.
  • Other compounds, such as a diluent can be added to the megestrol/surface stabilizer composition either before, during, or after the size reduction process.
  • Dispersions can be manufactured continuously or in a batch mode.
  • the nanoparticulate megestrol compositions of the invention may be used as an appetite stimulant to treat wasting conditions or cachexia.
  • wasting is used to mean a condition where the patient is losing body mass as a side effect of a disease progression, a disease treatment, or other condition. Examples of conditions where wasting is prevalent include, but are not limited to, HIV or AIDS, cancer, cachexia and anorexia.
  • nanoparticulate megestrol compositions of the invention may be used include, but are not limited to, neoplastic diseases where the disease normally regresses or the patient's symptoms are normally reduced in response to megestrol, or any other progestin.
  • the nanoparticulate megestrol compositions of the invention may also be used to treat conditions such as breast cancer, endometrial cancer, uterine cancer, cervical cancer, prostate cancer, and renal cancer.
  • cancer is used as one of ordinary skill in the art would recognize the term.
  • examples of cancers include, but are not limited to, neoplasias (or neoplasms), hyperplasias, dysplasias, metaplasias, and hypertrophies.
  • the neoplasms may be benign or malignant, and they may originate from any cell type, including but not limited to epithelial cells of various origin, muscle cells, and endothelial cells.
  • the present invention also provides methods of hormone replacement therapy in post-menopausal women, or in subjects after castration, comprising administering a nanoparticulate megestrol composition of the invention.
  • the compositions of the present invention may be used for ovarian suppression in several situations such as endometriosis, hirsutism, dysmenorrhea, and uterine bleeding.
  • the present invention also provides methods of oral contraception comprising administering a nanoparticulate megestrol composition of the invention.
  • the compositions of the invention are administered in combination with estrogen or a synthetic estrogen.
  • the nanoparticulate megestrol compositions of the invention can be administered to a subject via any conventional means including, but not limited to, orally, rectally, ocularly, parenterally (e.g ., intravenous, intramuscular, or subcutaneous), intracisternally, pulmonary, intravaginally, intraperitoneally, locally ( e.g ., powders, ointments or drops), or as a buccal or nasal spray.
  • parenterally e.g ., intravenous, intramuscular, or subcutaneous
  • intracisternally e.g ., intravenous, intramuscular, or subcutaneous
  • pulmonary intravaginally
  • intraperitoneally e.g ., powders, ointments or drops
  • buccal or nasal spray e.g a buccal or nasal spray.
  • subject is used to mean an animal, preferably a mammal, including a human or non-human.
  • patient and subject may be used interchangeably.
  • nanoparticulate megestrol compositions of the invention can be formulated into any suitable dosage form, including but not limited to liquid dispersions, gels, aerosols, ointments, creams, controlled release formulations, fast melt formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations.
  • Nanoparticulate megestrol compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • the nanoparticulate megestrol compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules.
  • the active agent is admixed with at least one of the following: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders, such as carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) solution retarders, such as paraffin; (g) absorption accelerators, such as quaternary ammonium compounds; (
  • Liquid nanoparticulate megestrol dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers.
  • Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • oils such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil
  • glycerol tetrahydrofurfuryl alcohol
  • polyethyleneglycols fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the present invention provides a method of achieving therapeutically effective plasma levels of megestrol in a subject at a lower dose than the standard commercial formulations. This can permit smaller dosing volumes depending on the megestrol concentration chosen.
  • Such a method comprises orally administering to a subject an effective amount of a nanoparticulate megestrol composition.
  • the nanoparticulate megestrol composition when tested in fasting subjects in accordance with standard pharmacokinetic practice, produces a maximum blood plasma concentration profile of megestrol of greater than about 30 ng/ml in less than about 5 hours after the initial dose of the composition.
  • maximum plasma concentration is interpreted as the maximum plasma concentration that megestrol will reach in fasting subjects.
  • a suitable dose of megestrol, administered according to the method of the invention is typically in the range of about 1 mg/day to about 1000 mg/day, or from about 40 mg/day to about 800 mg/day.
  • the therapeutically effective amount of the megestrol of this invention is about 1/6, about 1/5, about 1 ⁇ 4, about 1/3 rd, or about 1 ⁇ 2 of the therapeutically effective amount of existing commercial megestrol formulations, e . g ., Megace®.
  • “Therapeutically effective amount” as used herein with respect to a drug dosage shall mean that dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment. It is emphasized that "therapeutically effective amount,” administered to a particular subject in a particular instance will not always be effective in treating the diseases described herein, even though such dosage is deemed a “therapeutically effective amount” by those skilled in the art. It is to be further understood that drug dosages are, in particular instances, measured as oral dosages, or with reference to drug levels as measured in blood.
  • megestrol can be determined empirically and can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester, or prodrug form.
  • Actual dosage levels of megestrol in the nanoparticulate compositions of the invention may be varied to obtain an amount of megestrol that is effective to obtain a desired therapeutic response for a particular composition and method of administration.
  • the selected dosage level therefore depends upon the desired therapeutic effect, the route of administration, the potency of the administered megestrol, the desired duration of treatment, and other factors.
  • Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors: the type and degree of the cellular or physiological response to be achieved; activity of the specific agent or composition employed; the specific agents or composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the agent; the duration of the treatment; drugs used in combination or coincidental with the specific agent; and like factors well known in the medical arts.
  • D50 is the particle size below which 50% of the megestrol particles fall.
  • D90 is the particle size below which 90% of the megestrol particles fall.
  • the purpose of this example was to describe preparation of nanoparticulate dispersions of megestrol acetate.
  • Formulations 1, 2, 3, 4 and 5, shown in Table 1, were milled under high energy milling conditions using a NanoMill® (Elan Drug Delivery, Inc.) (see e.g ., WO 00/72973 for "Small-Scale Mill and Method Thereof") and a Dyno®-Mill (Willy Bachofen AG).
  • NanoMill® Elan Drug Delivery, Inc.
  • WO 00/72973 for "Small-Scale Mill and Method Thereof”
  • Dyno®-Mill Wang Bachofen AG
  • Formulations 1-5 showed small, well-dispersed particles using the Horiba La-910 Laser Scattering Particle Size Distribution Analyzer (Horiba Instruments, Irvine, CA) and light microscopy. Formulations 1-5 were stable in electrolyte fluids and had acceptable physical stability at 5°C for 4 weeks. Electrolyte fluids are representative of physiological conditions found in the human body. Formulations 1, 2, 3, and 4 also exhibited acceptable stability at 25°C and 40°C for 4 weeks. Formulation 5 exhibited acceptable stability at 40°C for at least 3 weeks.
  • This example compares the pharmacokinetic parameters of nanoparticulate megestrol acetate formulations of the present invention with conventional microparticulate formulations of megestrol acetate.
  • the dogs were subdivided into four groups, with each group receiving either Formulation A (nanoparticulate megestrol dispersion #1, comprising 4.0% megestrol acetate, 0.8% HPMC, and 0.4% DOSS), Formulation B (nanoparticulate megestrol dispersion #2, comprising 4.0% megestrol acetate, 0.8% HPMC, and 0.04% SLS), Formulation C (suspension of microparticulate megestrol acetate, Par Pharmaceutical, Inc., New York) or Formulation D (Megace® Oral Suspension, which is a suspension of microparticulate megestrol acetate). Each formulation was adjusted to administer a dose of 10 mg/kg of megestrol acetate to the subject.
  • Formulation A nanoparticulate megestrol dispersion #1, comprising 4.0% megestrol acetate, 0.8% HPMC, and 0.4% DOSS
  • Formulation B nanoparticulate megestrol dispersion #2, comprising 4.0% me
  • Formulation A with a C max of 2210, had a maximum concentration more than 4 1 ⁇ 2 times that of Formulation C (485), and a maximum concentration more than 6 1 ⁇ 2 times that of Formulation D (340).
  • Formulation B with a C max of 1563, had a maximum concentration more than 3.2 times that of Formulation C (485), and a maximum concentration more than 4.6 times that of Formulation D (340).
  • Formulation A with an AUC of 49,409 ng hr/mL, had an oral bioavailability more than 7 times that of Formulation C (6948 ng hr/mL) and an oral bioavailability of more than 4 times that of Formulation D (12007 ng hr/mL).
  • Formulation B with an AUC of 27,864 ng hr/mL, had an oral bioavailability more than 4 times that of Formulation C (6949 ng hr/mL) and an oral bioavailability more than 2 times that of Formulation D (12,007 ng hr/mL).
  • Formulation A with a T max of 0.83 hr, reached a maximum concentration of megestrol in less than 1/20 th the time of Formulation C (18.67 hr), and in less than 1/3 rd the time of Formulation D (2.67 hr).
  • Formulation B with a T max of 0.50 hr, reached a maximum concentration in less than 1/37 th the time of Formulation C (18.67 hr), and in less than 1/5 th the time of Formulation D (2.67 hr).
  • Formulation A with a C max of 3777, had a maximum concentration of about more than 1.7 times that of Formulation C (2181), and a maximum concentration of about more than 1.5 times that of Formulation D (2578).
  • Formulation B with a C max of 2876, had a maximum concentration of about more than 1.3 times that of Formulation C (2181), and a maximum concentration of about more than 1.1 times that of Formulation D (2578).
  • Formulation A with an AUC of 61,735 ng hr/mL, had an oral bioavailability of more than 1.9 times that of Formulation C (31721 ng hr/mL) and more than 1.5 times that of Formulation D (40219 ng hr/mL).
  • Formulation B with an AUC of 42788 ng hr/mL, had an oral bioavailability of more than 1.3 times that of Formulation C (31721 ng hr/mL) and an oral bioavailability of more than 1.1 times that of Formulation D (40218 ng hr/mL).
  • Megestrol acetate was milled under high energy milling conditions using a NanoMillTM2 System (Elan Drug Delivery, Inc.) in the presence of a preservative / buffer system consisting of sodium benzoate, citric acid monohydrate, and sodium citrate dihydrate. After milling, the resulting dispersion was diluted with water, sucrose, flavoring, and additional preservative / buffer to prepare dispersions containing 3% (w/w), 5% (w/w), or 9% (w/w) megestrol acetate. The resulting formulations are shown in Table 4.
  • the viscosities of the Formulations of this invention were found to be nearly Newtonian (i.e ., the viscosity being independent of shear rate), and were 1.5, 2.0, and 3.5 mPa s for the 30, 50, and 90 mg/mL concentrations, respectively.
  • the vial with the nanoparticulate dispersion shows a thin, silky, almost shear film coating the vial.
  • the vials containing the two commercial formulations show a gritty residue coating.
  • Such a gritty residue is the same residue which coats a patient's mouth and throat upon administration.
  • Such a coating is highly unpleasant, particularly for patients suffering from wasting ( i.e ., unable to eat).
  • Figure 3 visually demonstrates the appeal of a liquid oral nanoparticulate megestrol formulation of the invention as compared to conventional commercial liquid oral megestrol formulations.
  • the purpose of this example was to prepare nanoparticulate compositions of megestrol acetate using various surface stabilizers.
  • megestrol acetate 5% megestrol acetate (Par Pharmaceuticals, Inc.) was combined with 1.25% of various surface stabilizers: tyloxapol (Sterling Organics), Tween 80 (Spectrum Quality Products), Pluronic F-108 (BASF), Plasdone S-630 (ISP), hydroxypropylmethylcellulose (HPMC) (Shin Etsu), hydroxypropylcellulose (HPC-SL) (Nippon Soda Co., Ltd.), Kollidon K29/32 (polyvinylpyrrolidone) (ISP), or lysozyme (Fordras).
  • tyloxapol Steling Organics
  • Tween 80 Spectrum Quality Products
  • Pluronic F-108 BASF
  • ISP Plasdone S-630
  • HPMC hydroxypropylmethylcellulose
  • HPC-SL hydroxypropylcellulose
  • Kollidon K29/32 polyvinylpyrrolidone
  • lysozyme
  • the surface stabilizer was first dissolved in 7.875 g water for injection (WFI) (Abbott Laboratories, Inc.), followed by the addition of the milling media, PolyMillTM-500 (Dow Chemical, Co.), and 0.42 g megestrol.
  • WFI water for injection
  • the purpose of this example was to prepare nanoparticulate compositions of megestrol acetate using various surface stabilizers.
  • Megestrol acetate (Par Pharmaceuticals, Inc.) and various surface stabilizers, as shown in Table 8, were combined and milled, followed by determination of the particle size and stability of the resulting composition. Materials were obtained as in Example 6.
  • the physical stability was assessed by storing the dispersion is 20 ml glass scintillation vials in a temperature / humidity controlled chamber at either 5°C, (25°C / 60% RH), (40°C / 75% RH), (50°C /75% RH), or 55°C. Samples were taken at varying time intervals and the particle size was analyzed.
  • the surface stabilizer(s) was first dissolved in WFI (Abbott Laboratories, Inc.) (75.0 g for Exp. Nos. 1, 2, 3, 7, and 8; 75.2 g for Exp. Nos. 4 and 9; 74.9 g for Exp. Nos. 5 and 6; 70.3 g for Exp. Nos. 10 and 11), followed by combining the surface stabilizer solution megestrol acetate and PolyMillTM-500 polymeric grinding media. This mixture was then added to the appropriate milling chamber, milled for the time period shown in Table 8, followed by harvesting and vacuum filtering of the megestrol acetate dispersion. TABLE 8 Exp. No. Megestrol Conc. Surface Stabilizer(s) and Conc.
  • Milling Time Mean Particle Size Stability 1 5% 1.25% lysozyme 20 min. 209 nm The sample showed substantial aggregation after incubation in normal saline for 30 minutes as determined by optical microscopy. 2 5% 1.25% Tween 80 75 min. 157 nm Upon storage at 5°C for 15 days the sample grew to a mean diameter of 577 nm. 3 5% 1.25% tyloxapol 2 hrs. 208 nm Optical microscopoy revealed the presence of elongated "needle-like" crystals. 4 5% 1% Pluronic F127 2 hrs.
  • Tween 80, tyloxapol, and Pluronic F127 were effective primary surface stabilizers and produced well-dispersed particles without significant aggregation. Stability measurements, however, revealed rapid crystal growth for all three stabilizers. 5% megestrol acetate/1.25% Tween 80 grew from 157 nm to 577 nm after 15 days at 5°C. 5% megestrol acetate/1.25% tyloxapol showed needle-like crystals when observed under optical microscopy. 5% megestrol acetate/1.25% Pluronic F127 grew from 228 nm to 308 nm after 5 days at 25°C. Because of the rapid crystal growth observed, Tween 80, tyloxapol, and Pluronic F127 were deemed not suitable surface stabilizers at the described drug/surface stabilizer concentrations prepared under the conditions described above.
  • HPC-SL formulation (Exp. No. 8) showed substantial aggregation indicating that a secondary charged stabilizer would be needed.
  • SLS was added (Exp. No. 6) and the new formulation grew from 167 to 194 nm after storage at 40°C for 15 days and did not show any substantial aggregation upon incubation in either 0.01N HCl or normal saline. The SLS appeared effective at preventing the aggregation but the sample showed some particle size growth.
  • the HPMC formulation (Exp. No. 7) showed substantial aggregation indicating that a secondary charged stabilizer would be needed.
  • SLS was added (Exp. Nos. 5 and 11), and the new formulations showed only minimal growth from 161 nm to 171 nm (Exp. No. 5), and from 146 to 149 nm (Exp. No. 11), after storage at 40°C for 19 days.
  • the composition of Exp. No. 5 did not show any substantial aggregation upon incubation in either 0.01N HCl or normal saline.
  • the SLS was effective at preventing the aggregation without causing significant crystal growth.
  • DOSS Docusate sodium
  • the purpose of this example was to prepare nanoparticulate compositions of megestrol acetate using various surface stabilizers and further including preservatives or excipients.
  • Example 7 The materials and methods were the same as in Example 7, except that for several of the examples different sources of megestrol acetate were used (See Table 9). In addition, for Exp. Nos. 5 , a NanoMill® milling system (Elan Drug Delivery) was used. Several different combinations of megestrol acetate, surface stabilizer(s), and one or more preservatives or excipients were prepared, following by testing the compositions for particle size and stability.
  • the surface stabilizer(s) and one or more preservatives were first dissolved in WFI, followed by combining the solution with megestrol acetate and the grinding media. This mixture was then added to the milling chamber and milled for the time period set forth in Table 9, below.
  • the sample Upon storage at 40°C for 24 days, the sample showed aggregation with a mean diameter of 837 nm. Incubation for 30 minutes at 40°C in 0.01N HCl or normal saline resulted in particle sizes of 206 nm and 3425 nm, respectively. Optical microscopy confirmed that the sample incubated in saline had aggregated. 2 25% 5% HPMC 0.05% DOSS Sodium Benzoate (0.11 g) Citric Acid Monohydrate (0.08 g) 95 min. See right column. 16 g of the milled drug dispersion was combined with sucrose (5 g), lime flavor (80 mg), and WFI (78.9 g). The diluted drug dispersion had a mean diameter of 192.
  • a sweetened, flavored dispersion was prepared by mimicking the current commercial formulation of megestrol acetate that contains sucrose, xanthan gum, glycerol, lemon and lime flavors, and is preserved and buffered with sodium benzoate and citric acid.
  • megestrol acetate that contains sucrose, xanthan gum, glycerol, lemon and lime flavors, and is preserved and buffered with sodium benzoate and citric acid.
  • the sample showed aggregation with a mean diameter of 837 nm.
  • Incubation for 30 minutes at 40°C in 0.01N HCl or normal saline resulted in particle sizes of 206 nm and 3425 nm, respectively.
  • Optical microscopy confirmed that the sample incubated in saline had aggregated.
  • the aggregation upon storage indicated that this particular combination of drug and surface stabilizer, at the concentrations used and methodology employed to make the compositions, would not be an effective formulation.
  • Exp. Nos. 4 and 5 the formulation was scaled-up in a NanoMillTM-2 system to determine if the scale-up would effect the physical stability.
  • Two different sources of megestrol acetate were tested: Pharmacia and Pharmabios.
  • the product of Exp. No. 4 had a mean diameter of 160 nm without ultrasound. Upon storage at 50°C for 44 days the mean diameter was 190 nm.
  • the composition of Exp. No. 5 had a post-milling mean diameter of 147 nm without ultrasound. Upon storage at 50°C for 44 days the mean diameter was 178 nm. Both sources of active agent milled effectively and showed little particle size growth even at 50°C.
  • Examples 6 and 7 showed that high energy milling with polymeric attrition media could be used to produce stable nanoparticulate colloidal dispersions of megestrol acetate suitable for oral administration to animals or humans.
  • the primary stabilizer HPMC required the presence of DOSS or SLS to prevent aggregation at the concentrations of drug and stabilizer tested (other combinations of drug and HPMC concentrations may result in a stable composition without the addition of a second surface stabilizer). In general, average particle sizes of less than about 160 nm could be obtained. Tests conducted with two sources of megestrol acetate revealed that both sources milled effectively and exhibited excellent physical stability.
  • the best nanoparticulate megestrol acetate formulation for commercial development based on the results of the data given in the examples, consisted of 32.5% megestrol acetate, 6.5% HPMC, and 0.325% DOSS (i.e., a drug:HPMC ratio of 1:5 and a drug:DOSS ratio of 1:100.
  • the formulation milled effectively in the presence of preserved water (0.2% sodium benzoate, 0.01% sodium citrate dihydrate, and 0.15% citric acid monohydrate).
  • This example compares the pharmacokinetic parameters of nanoparticulate megestrol acetate formulations of the invention with a conventional microparticulate formulation of megestrol acetate. Results were obtained from a fasted study group consisting of 36 male subjects, 18 years of age or older. For a fed study group, results from 32 subjects were analyzed.
  • Treatment A (1 x 150 mg drug as 5 ml of a 3% megestrol acetate nanoparticulate formulation) was administered in the first period.
  • Reference Treatment B (1 x 800 mg drug as 20 ml of a 4% megestrol acetate Megace® Oral Suspension) was administered in the second period.
  • Treatment C (1 x 250 mg drug as 5 ml of a 5% megestrol acetate nanoparticulate formulation) was administered in the third period.
  • Treatment D (1 x 450 mg drug as 5 ml of a 9% megestrol acetate nanoparticulate formulation) was administered in the fourth period.
  • the formulations of Treatments A, C, and D are listed in Table 10 below, with particle size information (microns) provided in Table 11.
  • Plasma samples were obtained before dosing, at half-hourly intervals in the 6 hours following dosing, and at 7, 8, 12, 16, 20, 24, 36, 48, 72, and 96 hours after dosing. Megestrol acetate in plasma samples was then determined.
  • Table 12 summarizes pharmacokinetic data for the fasted study group
  • Table 13 summarizes pharmacokinetic data for the fed study group.
  • Treatments A, C, and D in fasting subjects produced dose-normalized values for AUC 0-t and AUC 0-inf that were approximately twice those of Reference Treatment B.
  • Maximum dose-normalized megestrol acetate concentrations in Treatments A, C, and D were approximately 9 to 12 times that of Reference Treatment B.
  • the maximum megestrol acetate concentration for the 150 mg-dose of Treatment A was approximately twice that of the 800 mg-dose of reference Treatment B.
  • comparable values of AUC 0-t and AUC 0-inf were observed for the 450 mg-dose of Treatment D and the 800 mg-dose of Reference Treatment B.
  • Treatments A, C, and D in fed subjects produced dose-normalized values for AUC 0-t and AUC 0-inf that were approximately 8 to 10% greater than those of Reference Treatment B.
  • Maximum dose-normalized megestrol acetate concentrations in Treatments A, C, and D were approximately 38 to 46% greater than that of Reference Treatment B.
  • Megestrol acetate onset for Treatments A, C, and D was comparable to Reference Treatment B.
  • Nanoparticulate megestrol acetate formulations therefore, exhibited superior oral bioavailability, relative to the Megace® Oral Suspension, in fasting and fed human subjects.
  • d(0.1) means distribution of smallest 10% of the particles, i.e., d(0.1) 10 ⁇ m means 10% of the particles are less than 10%.
  • d(0.5) means distribution of the smallest 50% of the particles, and
  • d(0.9) means distribution of the smallest 90% of the particles.
  • d(0.9) means that 90% of the particles are less than XX ⁇ m.
EP10010939.6A 2002-04-12 2003-04-14 Nanopartikuläre Megestrol- Formulierungen Withdrawn EP2263650A3 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US37168002P 2002-04-12 2002-04-12
US43034802P 2002-12-03 2002-12-03
EP03723991A EP1494649B1 (de) 2002-04-12 2003-04-14 Nanopartikuläre megestrol- formulierungen

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
EP03723991.0 Division 2003-04-14

Publications (2)

Publication Number Publication Date
EP2263650A2 true EP2263650A2 (de) 2010-12-22
EP2263650A3 EP2263650A3 (de) 2013-12-25

Family

ID=29254454

Family Applications (2)

Application Number Title Priority Date Filing Date
EP10010939.6A Withdrawn EP2263650A3 (de) 2002-04-12 2003-04-14 Nanopartikuläre Megestrol- Formulierungen
EP03723991A Expired - Lifetime EP1494649B1 (de) 2002-04-12 2003-04-14 Nanopartikuläre megestrol- formulierungen

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP03723991A Expired - Lifetime EP1494649B1 (de) 2002-04-12 2003-04-14 Nanopartikuläre megestrol- formulierungen

Country Status (10)

Country Link
EP (2) EP2263650A3 (de)
JP (2) JP4865990B2 (de)
AT (1) ATE539737T1 (de)
AU (1) AU2003230885A1 (de)
CA (1) CA2481390C (de)
CY (1) CY1113036T1 (de)
DK (1) DK1494649T3 (de)
ES (1) ES2380318T3 (de)
PT (1) PT1494649E (de)
WO (1) WO2003086354A1 (de)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9101540B2 (en) 2002-04-12 2015-08-11 Alkermes Pharma Ireland Limited Nanoparticulate megestrol formulations
US7879360B2 (en) 2003-11-05 2011-02-01 Elan Pharma International, Ltd. Nanoparticulate compositions having a peptide as a surface stabilizer
US20050131079A1 (en) * 2003-12-10 2005-06-16 Pujara Chetan P. Cefdinir oral suspension
ES2346755T3 (es) * 2004-12-01 2010-10-20 Par Pharmaceuticals, Inc. Uso de acetato de megestrol para mejorar la funcion cardiaca y el tratamiento de la insuficiencia cardiaca.
MX2007012778A (es) * 2005-04-12 2008-01-11 Elan Pharma Int Ltd Formulaciones de derivados de quinazolina nanoparticuladas.
EP1874267A1 (de) * 2005-04-13 2008-01-09 Pfizer Products Inc. Injizierbare depot-formulierungen und verfahren für die verzögerte freisetzung von schwerlöslichen arzneimitteln mit nanoteilchen
MX2008000396A (es) * 2005-06-22 2009-02-23 Elan Pharma Int Ltd Formulaciones de megestrol en nanoparticula.
EP1749531B1 (de) 2005-08-03 2015-07-22 Par Pharmaceuticals, Inc. Verwendung von einer oralen Suspension enthaltend Megestrolacetat zur Behandlung von Asthma bronchiale
BRPI0714173A2 (pt) * 2006-07-12 2012-12-25 Elan Pharma Int Ltd composiÇço nanoparticulada estÁvel,mÉtodos para preparar a composiÇço, para prevenir e/ou tratar estados de doenÇas, sintomas, sÍndromes e condiÇÕes do sistema nervoso central, para melhorar ou manter a biodisponibilidade de modafinil, e para tratar distérbio com base neurolàgica, composiÇço farmacÊutica, e forma de dosagem
AU2007325628A1 (en) * 2006-11-28 2008-06-05 Marinus Pharmaceuticals Nanoparticulate formulations and methods for the making and use thereof
WO2008129308A2 (en) * 2007-04-24 2008-10-30 Acacia Pharma Limited Drug combination and its use in the treatment of muscle loss
US9993427B2 (en) 2013-03-14 2018-06-12 Biorest Ltd. Liposome formulation and manufacture
CN111904931B (zh) * 2020-07-06 2022-09-20 中国人民解放军军事科学院军事医学研究院 一种醋酸甲地孕酮纳米晶口服混悬液及其制备方法和其应用

Citations (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4783484A (en) 1984-10-05 1988-11-08 University Of Rochester Particulate composition and use thereof as antimicrobial agent
US4826689A (en) 1984-05-21 1989-05-02 University Of Rochester Method for making uniformly sized particles from water-insoluble organic compounds
US5145684A (en) 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US5298262A (en) 1992-12-04 1994-03-29 Sterling Winthrop Inc. Use of ionic cloud point modifiers to prevent particle aggregation during sterilization
US5302401A (en) 1992-12-09 1994-04-12 Sterling Winthrop Inc. Method to reduce particle size growth during lyophilization
US5318767A (en) 1991-01-25 1994-06-07 Sterling Winthrop Inc. X-ray contrast compositions useful in medical imaging
US5326552A (en) 1992-12-17 1994-07-05 Sterling Winthrop Inc. Formulations for nanoparticulate x-ray blood pool contrast agents using high molecular weight nonionic surfactants
US5328404A (en) 1993-03-29 1994-07-12 Sterling Winthrop Inc. Method of x-ray imaging using iodinated aromatic propanedioates
US5336507A (en) 1992-12-11 1994-08-09 Sterling Winthrop Inc. Use of charged phospholipids to reduce nanoparticle aggregation
US5340564A (en) 1992-12-10 1994-08-23 Sterling Winthrop Inc. Formulations comprising olin 10-G to prevent particle aggregation and increase stability
US5346702A (en) 1992-12-04 1994-09-13 Sterling Winthrop Inc. Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization
US5349957A (en) 1992-12-02 1994-09-27 Sterling Winthrop Inc. Preparation and magnetic properties of very small magnetite-dextran particles
US5352459A (en) 1992-12-16 1994-10-04 Sterling Winthrop Inc. Use of purified surface modifiers to prevent particle aggregation during sterilization
US5399363A (en) 1991-01-25 1995-03-21 Eastman Kodak Company Surface modified anticancer nanoparticles
US5401492A (en) 1992-12-17 1995-03-28 Sterling Winthrop, Inc. Water insoluble non-magnetic manganese particles as magnetic resonance contract enhancement agents
US5429824A (en) 1992-12-15 1995-07-04 Eastman Kodak Company Use of tyloxapole as a nanoparticle stabilizer and dispersant
US5466440A (en) 1994-12-30 1995-11-14 Eastman Kodak Company Formulations of oral gastrointestinal diagnostic X-ray contrast agents in combination with pharmaceutically acceptable clays
US5472683A (en) 1995-03-09 1995-12-05 Eastman Kodak Company Nanoparticulate diagnostic mixed carbamic anhydrides as X-ray contrast agents for blood pool and lymphatic system imaging
US5500204A (en) 1995-02-10 1996-03-19 Eastman Kodak Company Nanoparticulate diagnostic dimers as x-ray contrast agents for blood pool and lymphatic system imaging
US5510118A (en) 1995-02-14 1996-04-23 Nanosystems Llc Process for preparing therapeutic compositions containing nanoparticles
US5518187A (en) 1992-11-25 1996-05-21 Nano Systems L.L.C. Method of grinding pharmaceutical substances
US5518738A (en) 1995-02-09 1996-05-21 Nanosystem L.L.C. Nanoparticulate nsaid compositions
US5521218A (en) 1995-05-15 1996-05-28 Nanosystems L.L.C. Nanoparticulate iodipamide derivatives for use as x-ray contrast agents
US5525328A (en) 1994-06-24 1996-06-11 Nanosystems L.L.C. Nanoparticulate diagnostic diatrizoxy ester X-ray contrast agents for blood pool and lymphatic system imaging
US5534270A (en) 1995-02-09 1996-07-09 Nanosystems Llc Method of preparing stable drug nanoparticles
US5543133A (en) 1995-02-14 1996-08-06 Nanosystems L.L.C. Process of preparing x-ray contrast compositions containing nanoparticles
US5552160A (en) 1991-01-25 1996-09-03 Nanosystems L.L.C. Surface modified NSAID nanoparticles
US5560931A (en) 1995-02-14 1996-10-01 Nawosystems L.L.C. Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5560932A (en) 1995-01-10 1996-10-01 Nano Systems L.L.C. Microprecipitation of nanoparticulate pharmaceutical agents
US5565188A (en) 1995-02-24 1996-10-15 Nanosystems L.L.C. Polyalkylene block copolymers as surface modifiers for nanoparticles
US5569448A (en) 1995-01-24 1996-10-29 Nano Systems L.L.C. Sulfated nonionic block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US5571536A (en) 1995-02-06 1996-11-05 Nano Systems L.L.C. Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5573749A (en) 1995-03-09 1996-11-12 Nano Systems L.L.C. Nanoparticulate diagnostic mixed carboxylic anhydrides as X-ray contrast agents for blood pool and lymphatic system imaging
US5573783A (en) 1995-02-13 1996-11-12 Nano Systems L.L.C. Redispersible nanoparticulate film matrices with protective overcoats
US5573750A (en) 1995-05-22 1996-11-12 Nanosystems L.L.C. Diagnostic imaging x-ray contrast agents
US5580579A (en) 1995-02-15 1996-12-03 Nano Systems L.L.C. Site-specific adhesion within the GI tract using nanoparticles stabilized by high molecular weight, linear poly (ethylene oxide) polymers
US5585108A (en) 1994-12-30 1996-12-17 Nanosystems L.L.C. Formulations of oral gastrointestinal therapeutic agents in combination with pharmaceutically acceptable clays
US5587143A (en) 1994-06-28 1996-12-24 Nanosystems L.L.C. Butylene oxide-ethylene oxide block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US5591456A (en) 1995-02-10 1997-01-07 Nanosystems L.L.C. Milled naproxen with hydroxypropyl cellulose as a dispersion stabilizer
US5593657A (en) 1995-02-09 1997-01-14 Nanosystems L.L.C. Barium salt formulations stabilized by non-ionic and anionic stabilizers
US5622938A (en) 1995-02-09 1997-04-22 Nano Systems L.L.C. Sugar base surfactant for nanocrystals
US5628981A (en) 1994-12-30 1997-05-13 Nano Systems L.L.C. Formulations of oral gastrointestinal diagnostic x-ray contrast agents and oral gastrointestinal therapeutic agents
US5643552A (en) 1995-03-09 1997-07-01 Nanosystems L.L.C. Nanoparticulate diagnostic mixed carbonic anhydrides as x-ray contrast agents for blood pool and lymphatic system imaging
US5662883A (en) 1995-01-10 1997-09-02 Nanosystems L.L.C. Microprecipitation of micro-nanoparticulate pharmaceutical agents
US5665331A (en) 1995-01-10 1997-09-09 Nanosystems L.L.C. Co-microprecipitation of nanoparticulate pharmaceutical agents with crystal growth modifiers
US5718919A (en) 1995-02-24 1998-02-17 Nanosystems L.L.C. Nanoparticles containing the R(-)enantiomer of ibuprofen
US5718388A (en) 1994-05-25 1998-02-17 Eastman Kodak Continuous method of grinding pharmaceutical substances
US5741522A (en) 1991-07-05 1998-04-21 University Of Rochester Ultrasmall, non-aggregated porous particles of uniform size for entrapping gas bubbles within and methods
US5747001A (en) 1995-02-24 1998-05-05 Nanosystems, L.L.C. Aerosols containing beclomethazone nanoparticle dispersions
US5834025A (en) 1995-09-29 1998-11-10 Nanosystems L.L.C. Reduction of intravenously administered nanoparticulate-formulation-induced adverse physiological reactions
US5862999A (en) 1994-05-25 1999-01-26 Nano Systems L.L.C. Method of grinding pharmaceutical substances
US6028065A (en) 1998-04-20 2000-02-22 Pharmaceutical Resources, Inc. Flocculated suspension of megestrol acetate
US6045829A (en) 1997-02-13 2000-04-04 Elan Pharma International Limited Nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers
US6068858A (en) 1997-02-13 2000-05-30 Elan Pharma International Limited Methods of making nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers
US6153225A (en) 1998-08-13 2000-11-28 Elan Pharma International Limited Injectable formulations of nanoparticulate naproxen
WO2000072973A1 (en) 1999-06-01 2000-12-07 Elan Pharma International Ltd. Small-scale mill and method thereof
US6165506A (en) 1998-09-04 2000-12-26 Elan Pharma International Ltd. Solid dose form of nanoparticulate naproxen
US6264922B1 (en) 1995-02-24 2001-07-24 Elan Pharma International Ltd. Nebulized aerosols containing nanoparticle dispersions
US6267989B1 (en) 1999-03-08 2001-07-31 Klan Pharma International Ltd. Methods for preventing crystal growth and particle aggregation in nanoparticulate compositions
US6268356B1 (en) 1998-04-20 2001-07-31 Pharmaceutical Resources, Inc. Flocculated suspension of megestrol acetate
US6270806B1 (en) 1999-03-03 2001-08-07 Elan Pharma International Limited Use of peg-derivatized lipids as surface stabilizers for nanoparticulate compositions
US6316029B1 (en) 2000-05-18 2001-11-13 Flak Pharma International, Ltd. Rapidly disintegrating solid oral dosage form
US20020012675A1 (en) 1998-10-01 2002-01-31 Rajeev A. Jain Controlled-release nanoparticulate compositions
US6375986B1 (en) 2000-09-21 2002-04-23 Elan Pharma International Ltd. Solid dose nanoparticulate compositions comprising a synergistic combination of a polymeric surface stabilizer and dioctyl sodium sulfosuccinate
US6428814B1 (en) 1999-10-08 2002-08-06 Elan Pharma International Ltd. Bioadhesive nanoparticulate compositions having cationic surface stabilizers

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1227626B (it) * 1988-11-28 1991-04-23 Vectorpharma Int Farmaci supportati aventi velocita' di dissoluzione aumentata e procedimento per la loro preparazione
US5338732A (en) * 1991-06-18 1994-08-16 Bristol-Myers Squibb Company Megestrol acetate formulation
FR2775435B1 (fr) * 1998-02-27 2000-05-26 Bioalliance Pharma Nanoparticules comprenant au moins un polymere et au moins un compose apte a complexer un ou plusieurs principes actifs
US20020028794A1 (en) * 2000-07-21 2002-03-07 Brubaker Greg Allen Megestrol acetate suspension
DE60223382T2 (de) * 2001-06-29 2008-09-11 Eurand Pharmaceuticals Ltd., Bray Verfahren für die thermodynamische aktivierung von wasserlöslichen arzneimitteln, die in vernetzten polymeren geladen sind
US7101576B2 (en) * 2002-04-12 2006-09-05 Elan Pharma International Limited Nanoparticulate megestrol formulations
JP2006507309A (ja) * 2002-10-31 2006-03-02 アルザ・コーポレーシヨン 疎水性薬剤の上昇した生物学的利用性を提供する製剤

Patent Citations (74)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4826689A (en) 1984-05-21 1989-05-02 University Of Rochester Method for making uniformly sized particles from water-insoluble organic compounds
US4997454A (en) 1984-05-21 1991-03-05 The University Of Rochester Method for making uniformly-sized particles from insoluble compounds
US4783484A (en) 1984-10-05 1988-11-08 University Of Rochester Particulate composition and use thereof as antimicrobial agent
US5451393A (en) 1991-01-25 1995-09-19 Eastman Kodak Company X-ray contrast compositions useful in medical imaging
US5145684A (en) 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US5494683A (en) 1991-01-25 1996-02-27 Eastman Kodak Company Surface modified anticancer nanoparticles
US5318767A (en) 1991-01-25 1994-06-07 Sterling Winthrop Inc. X-ray contrast compositions useful in medical imaging
US5552160A (en) 1991-01-25 1996-09-03 Nanosystems L.L.C. Surface modified NSAID nanoparticles
US5399363A (en) 1991-01-25 1995-03-21 Eastman Kodak Company Surface modified anticancer nanoparticles
US5776496A (en) 1991-07-05 1998-07-07 University Of Rochester Ultrasmall porous particles for enhancing ultrasound back scatter
US5741522A (en) 1991-07-05 1998-04-21 University Of Rochester Ultrasmall, non-aggregated porous particles of uniform size for entrapping gas bubbles within and methods
US5518187A (en) 1992-11-25 1996-05-21 Nano Systems L.L.C. Method of grinding pharmaceutical substances
US5349957A (en) 1992-12-02 1994-09-27 Sterling Winthrop Inc. Preparation and magnetic properties of very small magnetite-dextran particles
US5346702A (en) 1992-12-04 1994-09-13 Sterling Winthrop Inc. Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization
US5298262A (en) 1992-12-04 1994-03-29 Sterling Winthrop Inc. Use of ionic cloud point modifiers to prevent particle aggregation during sterilization
US5302401A (en) 1992-12-09 1994-04-12 Sterling Winthrop Inc. Method to reduce particle size growth during lyophilization
US5340564A (en) 1992-12-10 1994-08-23 Sterling Winthrop Inc. Formulations comprising olin 10-G to prevent particle aggregation and increase stability
US5336507A (en) 1992-12-11 1994-08-09 Sterling Winthrop Inc. Use of charged phospholipids to reduce nanoparticle aggregation
US5470583A (en) 1992-12-11 1995-11-28 Eastman Kodak Company Method of preparing nanoparticle compositions containing charged phospholipids to reduce aggregation
US5429824A (en) 1992-12-15 1995-07-04 Eastman Kodak Company Use of tyloxapole as a nanoparticle stabilizer and dispersant
US5352459A (en) 1992-12-16 1994-10-04 Sterling Winthrop Inc. Use of purified surface modifiers to prevent particle aggregation during sterilization
US5326552A (en) 1992-12-17 1994-07-05 Sterling Winthrop Inc. Formulations for nanoparticulate x-ray blood pool contrast agents using high molecular weight nonionic surfactants
US5401492A (en) 1992-12-17 1995-03-28 Sterling Winthrop, Inc. Water insoluble non-magnetic manganese particles as magnetic resonance contract enhancement agents
US5447710A (en) 1992-12-17 1995-09-05 Eastman Kodak Company Method of making nanoparticulate X-ray blood pool contrast agents using high molecular weight nonionic surfactants
US5328404A (en) 1993-03-29 1994-07-12 Sterling Winthrop Inc. Method of x-ray imaging using iodinated aromatic propanedioates
US5862999A (en) 1994-05-25 1999-01-26 Nano Systems L.L.C. Method of grinding pharmaceutical substances
US5718388A (en) 1994-05-25 1998-02-17 Eastman Kodak Continuous method of grinding pharmaceutical substances
US5525328A (en) 1994-06-24 1996-06-11 Nanosystems L.L.C. Nanoparticulate diagnostic diatrizoxy ester X-ray contrast agents for blood pool and lymphatic system imaging
US5587143A (en) 1994-06-28 1996-12-24 Nanosystems L.L.C. Butylene oxide-ethylene oxide block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US5585108A (en) 1994-12-30 1996-12-17 Nanosystems L.L.C. Formulations of oral gastrointestinal therapeutic agents in combination with pharmaceutically acceptable clays
US5628981A (en) 1994-12-30 1997-05-13 Nano Systems L.L.C. Formulations of oral gastrointestinal diagnostic x-ray contrast agents and oral gastrointestinal therapeutic agents
US6432381B2 (en) 1994-12-30 2002-08-13 Elan Pharma International Limited Methods for targeting drug delivery to the upper and/or lower gastrointestinal tract
US5466440A (en) 1994-12-30 1995-11-14 Eastman Kodak Company Formulations of oral gastrointestinal diagnostic X-ray contrast agents in combination with pharmaceutically acceptable clays
US5662883A (en) 1995-01-10 1997-09-02 Nanosystems L.L.C. Microprecipitation of micro-nanoparticulate pharmaceutical agents
US5665331A (en) 1995-01-10 1997-09-09 Nanosystems L.L.C. Co-microprecipitation of nanoparticulate pharmaceutical agents with crystal growth modifiers
US5560932A (en) 1995-01-10 1996-10-01 Nano Systems L.L.C. Microprecipitation of nanoparticulate pharmaceutical agents
US5569448A (en) 1995-01-24 1996-10-29 Nano Systems L.L.C. Sulfated nonionic block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US5571536A (en) 1995-02-06 1996-11-05 Nano Systems L.L.C. Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5593657A (en) 1995-02-09 1997-01-14 Nanosystems L.L.C. Barium salt formulations stabilized by non-ionic and anionic stabilizers
US5518738A (en) 1995-02-09 1996-05-21 Nanosystem L.L.C. Nanoparticulate nsaid compositions
US5534270A (en) 1995-02-09 1996-07-09 Nanosystems Llc Method of preparing stable drug nanoparticles
US5622938A (en) 1995-02-09 1997-04-22 Nano Systems L.L.C. Sugar base surfactant for nanocrystals
US5500204A (en) 1995-02-10 1996-03-19 Eastman Kodak Company Nanoparticulate diagnostic dimers as x-ray contrast agents for blood pool and lymphatic system imaging
US5591456A (en) 1995-02-10 1997-01-07 Nanosystems L.L.C. Milled naproxen with hydroxypropyl cellulose as a dispersion stabilizer
US5573783A (en) 1995-02-13 1996-11-12 Nano Systems L.L.C. Redispersible nanoparticulate film matrices with protective overcoats
US5560931A (en) 1995-02-14 1996-10-01 Nawosystems L.L.C. Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5543133A (en) 1995-02-14 1996-08-06 Nanosystems L.L.C. Process of preparing x-ray contrast compositions containing nanoparticles
US5510118A (en) 1995-02-14 1996-04-23 Nanosystems Llc Process for preparing therapeutic compositions containing nanoparticles
US5580579A (en) 1995-02-15 1996-12-03 Nano Systems L.L.C. Site-specific adhesion within the GI tract using nanoparticles stabilized by high molecular weight, linear poly (ethylene oxide) polymers
US5565188A (en) 1995-02-24 1996-10-15 Nanosystems L.L.C. Polyalkylene block copolymers as surface modifiers for nanoparticles
US5747001A (en) 1995-02-24 1998-05-05 Nanosystems, L.L.C. Aerosols containing beclomethazone nanoparticle dispersions
US5718919A (en) 1995-02-24 1998-02-17 Nanosystems L.L.C. Nanoparticles containing the R(-)enantiomer of ibuprofen
US6264922B1 (en) 1995-02-24 2001-07-24 Elan Pharma International Ltd. Nebulized aerosols containing nanoparticle dispersions
US5643552A (en) 1995-03-09 1997-07-01 Nanosystems L.L.C. Nanoparticulate diagnostic mixed carbonic anhydrides as x-ray contrast agents for blood pool and lymphatic system imaging
US5573749A (en) 1995-03-09 1996-11-12 Nano Systems L.L.C. Nanoparticulate diagnostic mixed carboxylic anhydrides as X-ray contrast agents for blood pool and lymphatic system imaging
US5472683A (en) 1995-03-09 1995-12-05 Eastman Kodak Company Nanoparticulate diagnostic mixed carbamic anhydrides as X-ray contrast agents for blood pool and lymphatic system imaging
US5521218A (en) 1995-05-15 1996-05-28 Nanosystems L.L.C. Nanoparticulate iodipamide derivatives for use as x-ray contrast agents
US5573750A (en) 1995-05-22 1996-11-12 Nanosystems L.L.C. Diagnostic imaging x-ray contrast agents
US5834025A (en) 1995-09-29 1998-11-10 Nanosystems L.L.C. Reduction of intravenously administered nanoparticulate-formulation-induced adverse physiological reactions
US6068858A (en) 1997-02-13 2000-05-30 Elan Pharma International Limited Methods of making nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers
US6221400B1 (en) 1997-02-13 2001-04-24 Elan Pharma International Limited Methods of treating mammals using nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors
US6045829A (en) 1997-02-13 2000-04-04 Elan Pharma International Limited Nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers
US6268356B1 (en) 1998-04-20 2001-07-31 Pharmaceutical Resources, Inc. Flocculated suspension of megestrol acetate
US6028065A (en) 1998-04-20 2000-02-22 Pharmaceutical Resources, Inc. Flocculated suspension of megestrol acetate
US6153225A (en) 1998-08-13 2000-11-28 Elan Pharma International Limited Injectable formulations of nanoparticulate naproxen
US6165506A (en) 1998-09-04 2000-12-26 Elan Pharma International Ltd. Solid dose form of nanoparticulate naproxen
US20020012675A1 (en) 1998-10-01 2002-01-31 Rajeev A. Jain Controlled-release nanoparticulate compositions
US6270806B1 (en) 1999-03-03 2001-08-07 Elan Pharma International Limited Use of peg-derivatized lipids as surface stabilizers for nanoparticulate compositions
US6267989B1 (en) 1999-03-08 2001-07-31 Klan Pharma International Ltd. Methods for preventing crystal growth and particle aggregation in nanoparticulate compositions
WO2000072973A1 (en) 1999-06-01 2000-12-07 Elan Pharma International Ltd. Small-scale mill and method thereof
US6431478B1 (en) 1999-06-01 2002-08-13 Elan Pharma International Limited Small-scale mill and method thereof
US6428814B1 (en) 1999-10-08 2002-08-06 Elan Pharma International Ltd. Bioadhesive nanoparticulate compositions having cationic surface stabilizers
US6316029B1 (en) 2000-05-18 2001-11-13 Flak Pharma International, Ltd. Rapidly disintegrating solid oral dosage form
US6375986B1 (en) 2000-09-21 2002-04-23 Elan Pharma International Ltd. Solid dose nanoparticulate compositions comprising a synergistic combination of a polymeric surface stabilizer and dioctyl sodium sulfosuccinate

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
"Cationic Surfactants: Physical Chemistry", 1991, MARCEL DEKKER
"Handbook of Phannaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain", 2000, THE PHARMACEUTICAL PRESS
"Physicians' Desk Reference for Nutritional Supplements", vol. 1, 2001
"Physicians Desk Reference", vol. 55, 2001
"Stedman's Medical Dictionary", 1990, WILLIAMS & WILKINS, pages: 935
"The Physicians' Desk Reference for Herbal Medicines", vol. 1, 2001
GARVER ET AL., J. P H?RM. SCI., vol. 74, no. 6, 1985, pages 664 - 667
J. CROSS, E. SINGER: "Cationic Surfactants: Analytical and Biological Evaluation", 1994, MARCEL DEKKER
J. RICHMOND: "Cationic Surfactants: Organic Chemistry", 1990, MARCEL DEKKER
LINDAHL ET AL.: "Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women", PHARM. RES., vol. 14, no. 4, 1997, pages 497 - 502
MARTINDALE'S: "The Extra Pharmacopoeia", 1996, THE PHARMACEUTICAL PRESS
ROBERTS ET AL.: "Nutraceuticals: The Complete Encyclopedia of Supplements, Herbs, Vitamins, and Healing Foods", 2001, AMERICAN NUTRACEUTICAL ASSOCIATION

Also Published As

Publication number Publication date
EP2263650A3 (de) 2013-12-25
JP4865990B2 (ja) 2012-02-01
CA2481390A1 (en) 2003-10-23
PT1494649E (pt) 2012-04-11
CA2481390C (en) 2012-11-27
WO2003086354A1 (en) 2003-10-23
ES2380318T3 (es) 2012-05-10
ATE539737T1 (de) 2012-01-15
EP1494649B1 (de) 2012-01-04
DK1494649T3 (da) 2012-04-10
JP2010248220A (ja) 2010-11-04
EP1494649A1 (de) 2005-01-12
AU2003230885A1 (en) 2003-10-27
JP2005527584A (ja) 2005-09-15
CY1113036T1 (el) 2016-04-13

Similar Documents

Publication Publication Date Title
US9040088B2 (en) Nanoparticulate megestrol formulations
US7101576B2 (en) Nanoparticulate megestrol formulations
EP1503737B1 (de) Nystatin-nanopartikelzusammensetzungen
EP1895984B1 (de) Nanoteilchenförmige imatinib-mesylat-formulierungen
US20130251805A1 (en) Low viscosity liquid dosage forms
US20070098805A1 (en) Methods of making and using novel griseofulvin compositions
US20110165251A1 (en) Liquid dosage compositions of stable nanoparticulate active agents
EP2279727A2 (de) Nanoteilchenförmige Aripiprazolformulierungen
EP1901728A2 (de) Acetaminophen-nanopartikelformulierungen
US20090291142A1 (en) Nanoparticulate bicalutamide formulations
JP2010248220A (ja) ナノ粒子メゲストロール製剤
EP1898882A2 (de) Nanopartikuläre ebastinformulierungen
US20120087955A1 (en) Nanoparticulate megestrol formulations
EP1935407A1 (de) Formen zur Dosierung einer Flüssigkeit mit geringer Viskosität

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AC Divisional application: reference to earlier application

Ref document number: 1494649

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

RIN1 Information on inventor provided before grant (corrected)

Inventor name: THE OTHER INVENTORS HAVE AGREED TO WAIVE THEIR ENT

Inventor name: PRUITT, JOHN

Inventor name: HOVEY, DOUGLAS

RIN1 Information on inventor provided before grant (corrected)

Inventor name: RYDE, TUULA

Inventor name: PRUITT, JOHN D.

Inventor name: HOVEY, DOUGLAS

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: ALKERMES PHARMA IRELAND LIMITED

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 31/57 20060101ALI20131118BHEP

Ipc: A61K 9/14 20060101AFI20131118BHEP

Ipc: A61P 35/00 20060101ALI20131118BHEP

Ipc: A61K 47/32 20060101ALI20131118BHEP

Ipc: A61K 47/38 20060101ALI20131118BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20140626